Trialkoxy quinazolines

ABSTRACT

A series of novel 2-substituted-4-amino-6,7,8trialkoxyquinazolines have been prepared, including their acid addition salts. These compounds are useful in therapy as potent antihypertensive agents. Methods for their preparation are described in detail, including various synthetic routes leading to the required novel intermediates.

United States Patent Hess 1 June 13, 1972 [54] TRIALKOXY QUINAZOLINESPrimary ExaminerAlex Mazel Assistant Examiner-R. J. Gallagher [72]Inventor. Hans Jurgen E. Hess, Old Lyme, Conn. Attorney connony and Hutz[73] Assignee: Pfizer Inc., New York, NY. 22 Filed: May 21, 1970 [57]ABSIRACT A series of novel 2-substituted-4-amino-6,7 8-trialkoxyquin- 4[211 App! No 39 5 l azolmes have been prepared, including their acidaddition salts. These compounds are useful in therapy as potent an- [52]US Cl- --2 /2 R, 2 /2 Q, 260/256-4 Q tihypertensive agents. Methods fortheir preparation are 424/200, 424/251 described in detail, includingvarious synthetic routes leading [51 I Int- Cl. ..C07d to the requirednovel intermediates [58] Field of Search ..260/256.4 Q, 256.5 R

15 Claims, N0 Drawings BACKGROUND OF THE INVENTION This inventionrelates to various new and useful trialkoxyquinazoline compounds, and totheir chemical method of preparation. More particularly, it is concernedwith a novel series of 2-substituted-4-amino-6,7,8-trialkoxyquinazolinesand their pharmaceutically acceptable acid addition salts, which are ofespecial value in medicine in view of their unique chemotherapeuticproperties.

In the past, various attempts have been made in the field of organicmedicinal chemistry to obtain new and useful antihypertensive agents.For instance, in copending US. Pat. application, Ser. No. 690,101, filedDec. 13, 1967, and now US. Pat. No. 3,511,836 issued May 12, 1970, thereare disclosed various 2,4-diamino-6,7-dimethoxyquinazoline compoundsuseful for these purposes. However, in the search for still newer andbetter antihypertensive agents, other attempts have proven to be lesssuccessful, e.g., the 8-monomethoxy, 6,7- methylenedioxy and6,7-ethylenedioxy derivatives in this series are all substantiallyinactive.

SUMMARY OF THE INVENTION In accordance with the present invention, ithas now been rather surprisingly found that various novel6,7,8-trialkoxyquinazoline compounds are extremely useful asantihypertensive agents, despite the aforesaid teaching indicated above,particularly regarding the 8-monomethoxy derivatives. More specifically,the novel compounds of this invention are all 2-substituted-4-amino-6,7,8-trialkoxyquinazolines of the formula:

and the acid addition salts thereof, wherein R is chosen from the groupconsisting of methyl and ethyl; and Z is a member selected from thegroup consisting of monoalkylamino and dialkylamino each having up tothree carbon atoms in the alkyl moiety, mono(/3-hydroxyethyl)amino anddi(B-hydroxyethyl)-amino, pyrrolidino, piperidino, homopiperidino andN-substituted piperazino ofthe formula:

wherein R is chosen from the group consisting of alkoxy having from oneto six carbon atoms, alkenyloxy having up to five carbon atoms andhydroxyalkoxy having from two to six carbon atoms, alkyl having from oneto six carbon atoms, phenyl, naphthyl, fury] and thienyl. These novelcompounds are all useful in reducing blood pressure of hypertensivesubjects.

Of special interest in this connection are such typical and preferredmember compounds of the invention as 2-(N-monomethylamino)-4-amino-6,7,8-trimethoxyquinazoline, 2-(N,N-dimethylamino )-4-amino-6,7,S-trimethoxy-quinazoline,2-[4-(2-furoyl)-l-piperazinyl]-4-amino-6,7,8-trimethoxyquinazoline,isobutyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)piperazine-l-carboxylate, 2-methyallyl 4-(4-amino-6,7,8-trimethoxyquinazolin-Zyl)piperazine-l-carboxylate and 2-methyl-Z-hydroxypropyl4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)piperazine-l-carboxylate, andtheir hydrochloride acid addition salts. All these compounds exhibithypotensive activity to a significantly high degree. In addition, theyhave a more favorable pharmacological profile e.g., they arenonadrenolytic in dogs) and possess greatly improved solubilitycharacteristics (particularly in water) as contrasted to thecorresponding 6,7-dialkoxy compounds reported in the prior art.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the processemployed for preparing the novel compounds of this invention, a2-halo-4-amino-6,7,8 5 trialkoxyquinazoline of the following structure:

where R is defined as aforesaid and X is a halogen atom selected fromthe group consisting of chlorine and bromine, is treated with anappropriate amine base of the formula ZH, where Z is as previouslydefined, to form the desired2-substituted-4-amino-6,7,8-trialkoxyquinazoline final product. Thisparticular reaction is normally carried out by using an excess of theamine base with respect to the required equimolar ratio, since thisserves to shift the reaction equilibrium to the product side of theequation. In addition, the excess amine can also function as a solventfor the reaction, with a preferred excess for these purposes being fromabout two to about ten moles of amine per one mole of2-halo-4-amino-6,7,8-trialkoxyquinazoline. On the other hand, areaction-inert polar organic solvent may also be used for the reactionand this would ordinarily entail employment of a cyclic ether such asdioxane and tetrahydrofuran, or a lower dialkylsulfoxide such as 3dimethyl and diethlsulfoxide, or a lower alkanol solvent like methanol,ethanol or isoamyl alcohol, etc. or even a N,N-dialkyl lower alkanoamidesuch as N,N-dimethylformamide, N,N- dimethylacetamide,N,N-diethylformamide and the like. The temperature at which the reactioncan be conducted varies widely within the range of from about 50 C. upto about 200 C. for a period of about I to about 12 hours. A preferredreaction time and temperature for the process at hand would be aboutl-l50 C. for about 2-4 hours. In the case where a particular solvent isused and/or the boiling point of the amine is below the desired reactiontemperature range, it is often customary in practice to employ a sealedpressure bottle as the proper vessel in which to conduct the reaction.Upon completion of same, recovery of the desired product is readilyeffected by any number of conventional means. For instance, the solventis evaporated from the mixture and the crude concentrate or resultingsolid residue is thereafter triturated with ethyl acetate or similarorganic solvent, In this way, high yields of trialkoxy-quinazoline finalproduct are obtained. It should 50 be noted in this connection that theamines (ZH) employed as reagent in this reaction are, for the most part,known compounds or else they can easily be prepared by those skilled inthe art from readily available starting materials, using the standardprocedures of organic chemistry.

pounds used as starting materials in the herein described process ofthis invention, such as 2-chloro and 2-bromo-4-amino-6,7,S-trimethoxyquinazoline, are themselves new compounds whichare prepared by treating the corresponding 2,4-

dihalo-6,7,8-trialkoxyquinazolines of the formula:

The 2-halo-4-amino-6,7,8-trialkoxyquinazoline base com- I of the desiredintermediate is readily accomplished using conventional means, such as,for example, partial evaporation of the solvent from the reactionmixture until incipient crystallization takes place, followed bytrituration of the resulting residue with water or by reprecipitation ofsaid residue from dilute aqueous acid. The2,4dihalo-6,7,B-trialkoxyquinazolines, on the other hand, are all newcompounds obtained by essentially known methods, starting from thecorresponding known 2-amino-3,4,5-trialkoxybenzoic acid and reacting thelatter type compound with either sodium or potassium cyanate in anaqueous acidic medium, followed by cyclization with aqueous base to formthe intermediate 6,7,8-trialkoxy- 2,4[1H,3H}-quinazolindione ringcompound, which, in turn, then yields the correspond-mg novel2,4-dihalo-6,7,8-trialkoxyquinoline on treatment with either phosphorusoxychloride or phosphorus oxybromide in accordance with the generalprocedure of F.H.S. Curd et al., as described in the Journal of theChemical Society (London), 1948, p. 1759.

As regards compounds of the invention where R of the N- substitutedpiperazine moiety is hydroxyalkoxy, as previously defined, a preferredand alternate method of preparation simply involves treating thecorresponding compounds where R is alkenyloxy, as obtained by theprincipal process of this invention, with water in the presence of atleast a catalytic amount of concentrated sulfuric acid to form thedesired secondary or tertiary alcohol, as the case may be, in accordancewith the standard methods of organic chemistry. A preferred temperaturerange for this reaction would normally be from about -20 C. In this way,a compound such as 2- methylallyl4-(4-amino-6,7,8-tri-methoxyquinazolin-2- yl)piperazine-l-carboxylate isconverted to 2-methyl-2- hydroxypropyl 4-( 4-amin o-6,7 ,S-trimethoxyquinazolin-2- yl)piperazine-l-carboxylate in a most facile manner, as ishereinafter described in more detail in the examples which follow.

Inasmuch as the 2-substituted-4-amino-6,7,8-tria.lkoxyquinazolinecompounds of this invention are basic compounds, they are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must first be pharmaceuticallyacceptable for administration to animals, it is often desirable inpractice to initially isolate the2-substituted-4-amino-6,7,8-trialkoxyquinazoline base compound from thereaction mixture as a pharmaceuticaliy unacceptable salt and then simplyconvert the latter back to the free base compound by treatment with analkaline reagent and thereafter, subsequently convert the latter freebase to a pharmaceutically acceptable acid addition salt. The acidaddition salts of the 2-substituted-4-amino-6,7,8-trialkoxyquinazolinebase compounds of this invention are readily prepared by treating thebase compound with an equivalent amount of the chosen acid in an aqueoussolution or in a suitable organic solvent, such as methanol or ethanol.Upon evaporation of the solvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the aforementioned2-substituted-4-amino-6,7,8-trialkoxyquinazoline base compounds of thisinvention are those which form non-toxic acid addition salts, i.e.,salts containing pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate,phosphate or acid phosphate, acetate, lactate, citrate or acid citrate,tartrate or bitartrate, succinate, maleate, fumarate, gluconate,saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluene-sulfonate and pamoate [i.e., 1,1- methylene-bis(2-hydroxy-3-naphthoate)]salts.

As previously indicated, the 2-substituted-4-amino-6,7,8-trialkoxyquinazoline compounds of the present invention are all readilyadapted to therapeutic use as antihypertensive agents, particularly inview of their ability to lower the blood pressure of hypertensivesubjects to a statistically significant degree. For instance,2-methyl-2-hydroxypropyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)piperazinel -carboxylate, a typical andpreferred agent of the present invention, has been found to lower theblood pressure of conscious hypertensive dogs to a statisticallysignificant degree e.g., up to 42 mm. Hg. after 2 hours subsequent todrug administration) when given by the oral route of administration atincreasing dose levels ranging from 2.5-40 mg./kg., daily, for a periodof up to four days. Additionally, these compounds are well absorbed inthe body and none of them cause any substantial side effects to occur inthe subject to whom they are administered, i.e., no problems of toxicityor of an untoward pharmacological nature, like postural hypotension, areever encountered when said compounds are administered for theaforestated purpose in the manner described as indicated above.

In accordance with a method of treatment of the present invention, theherein described 2-substituted4-amino-6,7,8-trialkoxyquinazolineanti-hypertensive agents can be administered to a hypertensive subjectvia either the oral or parenteral routes of administration. In general,these compounds are most desirably administered in doses ranging fromabout 10 mg. up to about 600 mg. per day, although variations will stillnecessarily occur depe.iding upon the weight of the subject beingtreated. However, a dosage level that is in the range of from about 0.16mg. to about 9.6 mg. per kg. of body weight per day is most desirablyemployed in order to achieve effective results, with a preferred oralrange in man being about 2.5-5.0 mg./kg. Nevertheless, it is still to beappreciated that other variations may also occur in this respect,depending upon the species of animal being treated and its individualresponse to said medicament, as well as on the particular type ofpharmaceutical formulation chosen and the time period and interval atwhich such administration is carried out. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful or deleterious side effects to occurprovided that such higher dose levels are first divided into severalsmaller doses that are to be administered throughout the day.

in connection with the use of the 2 substituted-4-amino-6,7,8-trialkoxyquinazoline compounds of this invention for the treatmentof hypertensive subjects, it is to be noted that they may beadministered either alone or in combination with pharmaceuticallyacceptable carriers by either of the routes previously indicated, andthat such administration can be carried out in both single and multipledosages. More particu larly, the novel compounds of the invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically-acceptable inert carriers inthe form of tablets, capsules, lozenges, troches, hard candies, powders,aqueous suspensions, injectable solutions, elixirs, syrups, and thelike. Such carriers include solid diluents or fillers, sterile aqueousmedia and various non-toxic organic solvents, etc. Moreover, such oralpharmaceutical compositions can be suitably sweetened and/or flavored bymeans of various agents of the type commonly employed for just such apurpose. In general, the therapeutically-effective compounds of thisinvention are present in such dosage forms at concentration levelsranging from about 0.5 percent to about percent by weight of the totalcomposition, i.e., in amounts which are sufficient to provide thedesired unit dosage.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and dicalciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in soft and hardfilled gelatin capsules; preferred materials in the connection wouldalso include lactose or milk sugar, as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the essential active ingredient thereinmay be combined with various sweetneing or flavoring agents, coloringmatters or dyes, and, if so desired, emulsifying and/or suspendingagents as well, together with such diluents as water, ethanol, propyleneglycol, glycerin and various like combinations thereof.

For purposes of parenteral administration, solutions of these particular2-substituted-4-amino6,7,8-trialkoxyquinazolines in either sesame orpeanut oil or in aqueous propylene glycol may be employed, as well assterile aqueous solutions of the corresponding water-soluble, non-toxicmineral and organic acid addition salts previously enumerated. Suchaqueous solutions should be suitably buffered if necessary and theliquid diluent first rendered isotonic with sufiicient saline orglucose. These particular solutions are especially suitable forintravenous, intramuscular and subcutaneous injection purposes.

PREPARATION A A solution consisting of 65.3 g. (0.805 mole) of potassiumcyanate dissolved in 200 ml. of water was added with stirring, duringthe course of a -minute period, to a suspension of 112 g. (0.535mole) of2-amino-3,4,5-trimethoxybenzoic acid [obtained by saponification, with1N NaOH in methanolwater (4:1 by volume), of the corresponding knownmethyl ester] in 2.6 liters of water containing 46 ml. of glacial aceticacid, while maintaining the temperature of the mixture at ca. 30 C.throughout the course of the addition. The resulting reaction mixturewas then stirred at this same temperature for 2 hours, followed by thesubsequent addition of 746 mg. (18.3 moles) of sodium hydroxide(pellets) thereto with aid of gentle external cooling to maintain thetemperature below (or near) 40 C. The resulting suspension wasthereafter stirred for 1 hour at room temperature C.) and finally,acidified with concentrated hydrochloric acid, with external coolingbeing required to keep the temperature below 25 C. The final mixture wasstirred at this point for 1 hour and filtered, and the solid residuethus obtained (i.e., the filter cake) was subsequently washed with waterand airdried before being ground to a fine powder. After drying thelatter material to constant weight in vacuo over P 0 there was obtaineda 135 g. (87 percent) yield of 6,7,8trimethoxy-2,4[1H,3Hlquinazolindione in the form of a yellow crystalline powder, m.p.259262 C. Recrystallization of the product from dimethylformamide-waterthen gave fine white plates, m.p. 266-269 C.

Anal. Calcd. forC H N o C, 52.38; H, 4.80;N, 11.11.

Found: C, 51.86; H, 4.78; N, 11.30.

PREPARATION B The procedure described in Preparation A is repeatedexcept that 2-amino-3,4,5-triethoxybenzoic acid is the starting materialemployed in place of the corresponding trimethoxy acid. In thisparticular case, the corresponding final product obtained is6,7,8-triethoxy-2,4[1H, 3H]quinazolindione.

EXAMPLE I A mixture consisting of 70.0 g. (0.278 mole) of 6,7,8-trimethoxy-2,4-[ 1H, 3H]-quinazolindione (m.p. 259-262 C.) and 1,100 m1.of phosphorus oxychloride was heated to reflux with stirring for aperiod of 2 hours. At the end of this time, the resulting clear solutionwas concentrated under reduced pressure and the residue thus obtainedwas dissolved in ca. 750 ml. of chloroform. The chloroform solution wasslowly poured, with stirring, into an excess of saturated aqueous sodiumbicarbonate and the resulting mixture vigorously stirred until evolutionof carbon dioxide gas virtually ceased. The chloroform layer was thenseparated from the mixture and combined with two subsequent chloroformextracts (750 ml.) of the aqueous phase. The combined chloroformextracts were then washed with water, dried over anhydrous sodiumsulfate and filtered to give a dry organic filtrate that wassubsequently concentrated under reduced pressure to yield 73.0

g. (91 percent) of 2,4-dichloro-6,7,8-trimethoxyquinazoline (m.p.l48-151C.) as a tan crystalline residue. Recrystallization of the lattermaterial from ethanol then gave fine white needles, mp. 147-l50 C.

Anal. Calcd. for C H CI N Q; C, 45.99; H, 3.48; N, 9.68; C1, 24.52.

Found: C, 45.48; H, 3.14; N, 9.76; Cl, 24.60.

EXAMPLE II The procedure described in Example I is repeated except that6,7,8-triethoxy-2,4[1H, 3H]-quinazolindione is the starting materialemployed and 2,4-dichloro-6,7,8-tri-ethoxyquinazoline is thecorresponding final product thus obtained.

EXAMPLE III The procedure described in Example I is repeated except thatphosphorus oxybromide is the actual reagent employed in lieu ofphosphorus oxychloride and 2,4-dibromo-6,7,8- trimethoxyquinazoline isthe corresponding final product thus obtained.

In like manner, 6,7,8-triethoxy-2,4[1H, 3H]-quinaz0lindione andphosphorus oxybromide react in accordance with this procedure to afford2,4-dibromo-6,7,8-triethoxyquinazoline.

EXAMPLE IV A vigorously stirred solution of 2,4-dichloro-6,7,8-trimethoxyquinazoline (73.0 g., m.p. l48-15l C.) in tetrahydrofuran wastreated with anhydrous ammonia by passing said gas through the solutionfor a period of 2 hours. The resulting reaction mixture was then stirredat room temperature 25 C.) for a period of 16 hours and finally,concentrated under reduced pressure to afford a solid residue. Thelatter material was subsequently triturated with car. 500 m1. of waterand the resulting aqueous suspension thereafter filtered. The residualfilter cake was then washed with water and partially air-dried, beforebeing suspended in hot ethanol. The latter alcoholic suspension was thencooled and filtered to give, after drying to constant weight, 56.2 g.(75 percent) of 2- chloro-4-amino-6,7,8-trimethoxyquinazoline in theform of pure white crystals, m.p. 243-246 C. Recrystallization of thelatter material from ethanol then raised the melting point to 244-246 C.

Anal. Calcd. for C,,H,,C1N,0,; C, 48.99; H, 4.49; N, 15.58; Cl, 13.15.

Found: C, 48.95; H, 4.53; N, 15.65; Cl, 13.09.

EXAMPLE V The procedure described in Example IV is repeated except that2,4-dichloro-6,7,8-triethoxyquinazoline is the starting materialemployed and 2-chloro-4-amino-6,7,8-triethoxyquinazoline is thecorresponding final product thus obtained.

EXAMPLE VI The procedure described in Example IV is repeated except that2,4-dibromo-6,7,8-trimethoxyquinazoline is the starting materialemployed and 2-bromo-4-amino-6,7,8-trimethoxyquinazoline is thecorresponding final product thus obtained.

In like manner, 2,4-dibromo-6,7,8-triethoxyquinazoline and anhydrousammonia react in accordance with this procedure to afford2-bromo-4-amino-6,7,8triethoxyquinazoline.

EXAMPLE VII A mixture consisting of 8.08 g. (0.030 mole) of 2-chloro-4-amino-6,7,S-triemthoxyquinazoline (m.p. 243-246 C.) and 5.88 g. (0.033mole) of 2-methylallyl l-piperazinecarboxylate in 200 m1. of isoamylalcohol was heated to reflux for a period of 75 minutes. The resultingmixture was then cooled and concentrated under reduced pressure toafford an amorphous residue, which was subsequently triturated withethyl acetate. The residue thus obtained was recovered by means offiltration and washed with ethyl acetate to give, after air drying toconstant weight, 12.6 g. (93 percent) of 2-methylallyl 4-(4- amino-6,7,8-trimethoxyquinazolin-2 -yl )piperazinel -carboxylate as the purehydrochloride salt, in the form of white crystals melting at 186188C.(dec.). Recrystallization of the product from ethanolic hydrochloricacid did not raise the melting point.

Anal. Calcd. for c,.,H,,N,o,-Hc1= C, 52.92; H, 6.22; N, 15.43; Cl, 7.81.

Found: C, 52.83; H, 6.47; N, 15.45; Cl, 7.82.

Subsequent conversion of the above hydrochloride salt to thecorresponding free organic base was then accomplished by dissolving 7.6g. of said product in water-ethanol (9:1 by volume), followed bytreatment with an excess of saturated aqueous sodium bicarbonatesolution. The essentially pure free base compound was then separatedfrom the resulting mixture by means of filtration, and washed with waterand airdried to give 6.8 g. (97 percent) of 2-methylallyl 4-(4-amino-6,7,8-trimethoxyquinazolin-Z-yl )-piperazinel -carboxylate in the formof pure white crystals, m.p. 170-l 73 C. Recrystallization of the lattermaterial from chloroform-diisopropyl ether then raised the melting pointto l72174 C.

Anal. Calcd. for C H N O C, 57.54; H, 6.52; N, 16.78.

Found: C, 57.06; H, 6.44; N, 16.43.

EXAMPLE VIII A stirred solution consisting of 24 ml. of concentratedsulfuric acid dissolved in an equal volume of water was cooled to ca. l2C. and treated with 6.25 g. (0.015 mole) of 2-methylallyl4-(4-amino-6,7,8-trimethoxyquinazolin-Z-yl)piperazine-1- carboxylateadded in small portions, with stirring being maintained throughout thecourse of the addition at such a rate as to always keep the temperatureof the reaction mixture below 20 C. The resulting mixture was thenfurther stirred for 15 minutes,while at 18 C., to give a clear solution,which was subsequently stirred for an additional two hours at lO-15 C.The aqueous solution thus obtained was then diluted with 150 ml. ofice-water and adjusted to a pH of ca. with 50 percent aqueous sodiumhydroxide, while maintaining the temperature below 12 C. throughout thisstep. The resulting alkaline mixture was next extracted with four 150ml. portions of chloroform, and the chloroform extracts were combined,washed with water and then dried over anhydrous sodium sulfate. Afterremoval of the drying agent by means of filtration and the organicsolvent by means of evaporation under reduced pressure, there wasultimately obtained a white crystalline solid as residue. The yield ofproduct amounted to 6.0 g. and it melted at 15 l-l 15 C.Recrystallization of this material from chloroform-diisopropyl etherthen gave 5.0 g. (77 percent) of pure 2-methyl-2hydroxypropyl4-(4-amino- 6,7,8-trimethoxyquinazolin-Z-yl)piperazine-l-carboxylate, aswhite crystals melting at l56-l59 C. A further recrystallization fromthe same solvent system then raised the melting point to 158-l59 C.

Anal. Calcd. for C H N O C, 55.16; H, 6.71; N, 16.08.

Found: C, 55.09; H, 6.62; N, 15.84.

Treatment of the above free organic base (4.5 g.) in ethanol withethanolic hydrochloric acid in the cold (cooling being effected by meansof an ice-water bath) then gave 3.24 g. (66 percent) of2-methyl-2-hydroxypropyl 4-(4-amino-6,7,8- trimethoxyquinazolin-Z-yl)piperazine- 1 -carboxylate hydrochloride, as white crystals melting atl66-l69 C. (dec.).

Anal. Calcd. for C H N O 'HCl-H O: C, 49.03; H, 6.58; N, 14.29; Cl,7.24.

Found: C, 48.88; H, 6.63; N, 14.32; C], 7.36.

EXAMPLE IX The procedure described in Example VII was repeated toprepare the following2-substituted-4-amino-6,7,8-trimethoxyquinazolines, reported ashydrochlorides, starting from 2-chloro-4-amino'6,7,8-triemthoxyquinazoline and the appropriate primaryor secondary organic amine reagent in each case:

2-( N-monomethylamino )-4-amino-6,7,8-trimethoxyquinazolinehydrochloride, m.p. 22923 1 C.

2-( N,N-dimethylamino )-4-amino-6,7,8-trimethoxyquinazolinehydrochloride, m.p. 237-239 C.

2-(N,N-diethylamino )-4-arnino-6,7,8-trimethoxyquinazoline hydrochoride,m.p. l86-l 88 C.

2-[ N,N-di-( n-propyl)amino]-4-amino-6,7,8-trimethoxyquinazolinehydrochloride, m.p. 20l-203 C.

2-[ N,N-di(fi-hydroxyethyl )amino -4-amino-6,7,8- trimethoxyquinazolinehydrochloride, m.p. 220222 C.

2-(N-pyrrolidino)-4-amino-6,7,8-trimethoxyquinazoline hydrochloride,m.p. 21 8220 C.

2-(N-piperidino)-4-amino-6,7,S-trimethoxyquinazoline hydrochloride, m.p.219-221 C.

2-(N-homopiperidino)-4-amino-6,7,8-trimethoxyquinazoline hydrochloride,m.p. l86-l89 C.

2-( 4-benzoyll -piperazinyl )-4-amino6,7 8-trimethoxyq ninazolinehydrochloride, m.p. 175 '1 77 C.

2-[4-( 2-furoyl l -piperazin yl]-4-amino-6,7,8-trimethoxyquinazolinehydrochloride, m.p. 208209 C.

ethyl 4-( 4-amino-6,7,8-trimethoxyquinazolin-Z-ylpiperazine-l-carbonylate hydrochloride, m.p. 228-230 C.

isobutyl 4-( 4-amino-6,7,8 trimethoxyq uinazolin-2-ylpiperazine-l-carboxylate late hydrochloride, m.p. l90l 92 C.

Subsequent conversion of each of the above hydrochloride salts to thecorresponding free organic base compound, in each case via saturatedaqueous sodium bicarbonate solution in the manner of Example Vll,thenaffords the corresponding2-substituted-4-amino-6,7,B-trimethoxyquinazoline in pure form as such.

EXAMPLE X The procedure described in Example VII is employed again toprepare the following 2-substituted-4-amin0-6,7,8-trialkoxyquilazolines, starting from the corresponding 2-chloro-4-amino-6,7,8-trialkoxyquinazoline compound and the appropriate aminereagent in each instance:

The procedure described in the previous examples is employed once againto prepare the following 2-substituted-4-amino-6,7,8-trialkoxyquinazolines, starting from the corresponding2-chloro-4-amino-6,7,8-t1ialkoxyquinazoline compound and the appropriatel-piperazinecarboxylate reagent in each instance:

The procedure described in Example VII is employed once again to preparethe final products of Examples VII and IX-XI by merely using theappropriate 2-bromo-4-amino-6,7,8-trialkoxyquinazoline compound, inplace of the corresponding 2- chloro compound, as proper startingmaterial for the reaction. In each and every case, the final productthus obtained (i.e., the2-substituted-4-amino-6,7,8-trialkoxyquinazoline compound) is found tobe identical with that reported previously for the correspondingreaction in the aforesaid examples. For instance,2-bromo-4-amino-6,7,8-trimethoxyquinazoline and 2-methallyll-piperazinecarboxylate react in this manner to afford 2-methallyl4-(4-amino-6,7,8-trimethoxyquinazolin-2- yl)piperazine-l-carboxylate,identical in every respect with the product of Example VII.

EXAMPLE XIII The other hydrohalide acid addition salts of the2-substituted-4-amino-6,7,8-tria.lkoxyquinazoline base compounds of thisinvention reported previously, such as the corresponding hydrochloride,hydrobromide and hydriodide salts, are each individually prepared byfirst dissolving the respective organic base compound in absolute etherand then adding a saturated solution of the appropriate hydrohalide gasin ethyl acetate to the aforementioned ethereal solution, whereupon thedesired acid addition salt soon precipitates from said solution. In thisway, 2-methyl-2-hydroxypropyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)piperazine-l-carboxylate (1.0 g.)

is converted via dry hydrogen bromide gas to the correspondinghydrobromide acid addition salt in almost quantitative yield.

EXAMPLE XIV The nitrate, sulfate or bisulfate, phosphate or acidphosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, methanesulfonate,ethanesulfonate, benzensulfonate, p-toluenesulfonate and parnoate [i.e.,1,1 -methylene-bis(2-hydroxy-3- naphthoate)]salts of each of theaforementioned 2-substituted-4-amino-6,7,8-trialkoxyquinazoline basecompounds reported previously are each prepared by dissolving the propermolar amounts of the respective acid and base in separate portions ofethanol and then mixing the two solutions together, followed by theaddition of diethyl ether to the resultant solution in order to effectprecipitation of the desired acid addition salt therefrom. In thismanner, equimolar amounts of2-(N,N-dimethylamino)-4-amino-6,7,8-trimethoxyquinazoline andconcentrated sulfuric acid react to afford the corresponding sulfuricacid addition salt. In like manner, each of the other salts is alsosimilarly prepared.

EXAMPLE XV A dry solid pharmaceutical composition is prepared byblending the following materials together in the proportions by weightspecified below:

2-Methyl-2-hydroxypropyl4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)piperazine-l-carboxylatehydrochloride 0 Sodium citrate 25 Alginic acid l0 Polyvinylpyrrolidone il0 Magnesium stearate 5 After the dried mixture is thoroughly blended,tablets are punched from the resulting mixture, each tablet being ofsuch size that it contains 50 mg. of the active ingredient. Othertablets are also prepared in a similar fashion containing 5, l0 and 25mg. of the active ingredient, respectively, by merely using theappropriate amount of the trialkoxy-quinazoline compound in each case.

EXAMPLE XVI A dry solid pharmaceutical composition is prepared bycombining the following materials together in the proportions by weightindicated below:

2-[4-( 2-Furoyl)-lpiperazinyl]-4-amino-6,7,8-trimethoxyquinazolinehydrochloride 50 Calcium carbonate 20 Polyethylene glycol, averagemolecular weight 4000 i 30 The dried solid mixture so prepared is thenthoroughly agitated so as to obtain a powdered product that iscompletely uniform in every respect. Soft elastic and hard-filledgelatin capsules containing this pharmaceutical composition are thenprepared, employing a sufficient quantity of material in each instanceso as to provide each capsule with mg. of the active ingredient.

EXAMPLE XVII The following2-substituted-4-amino-6,7,8-trimethoxyquinazolines were tested forhypotensive activity in conscious hypertensive dogs by the procedure ofPrioli and Winbury, as described in the Journal of Applied Physiology,Vol. 15, p. 323 (1960) and found to be effective at the indicatedconcentration levels by both the oral and intravenous routes. Thecompounds were administered in the form of their hydrochloride salts andthe blood pressure determinations were made just prior to and atfrequent intervals after drug administration (e.g., at 2, 4 and 24 hoursthereafter), using at least two or more dogs for the evaluation of eachcompound. The activity is therefore expressed in terms of the observedrange in reduction of blood pressure in mm. Hg in two or more dogs,while the concentration levels are reported as mgjkg. per dose.

N-hornopiperidino -20(2), -50 (4) 0-1 5( l0), 0-ll5(20) EXAMPLE XVIIIThe test procedure described in the previous example was repeated hereto determine the hypotensive activity of the following2-substituted-4-amino-6,7,S-trimethoxyquinazolirxe compounds, and theresults obtained in this manner are re- What is claimed is:

l. A compound selected from the group consisting of2-substituted-4-amino-6,7,8-trialkoxyquinazoline bases of the formula:

and the pharmaceutically acceptable acid addition salts thereof, whereinR is chosen from the group consisting of methyl and ethyl; and Z is amember selected form the group consisting of monoalkylamino anddialkylamino each having up to three carbon atoms in the alkyl moiety,monoUS-hydroxyethyl)amino and di(fl-hydroxyethyl)amino, pyrrolidino,piperidino, homopiperidino and N-substituted piperazino of the formula:

wherein R is chosen from the group consisting of alkoxy having from oneto six carbon atoms, alkenyloxy having up to five carbon atoms andhydroxyalkoxy having from two to six carbon atoms, alkyl having from oneto six carbon atoms, phenyl, naphthyl, furyl and thienyl.

2. A compound as claimed in claim 1 wherein Z is monoalkylamino.

3. A compound as claimed in claim 1 wherein Z is di-alkylamino.

4, 2-(N-Monomethylamino)-4-amino-6,7,8-trimethoxyquinazoline.

5. 2-(N,N-Dimethylamino)-4-amino-6,7,S-trimethoxyquinazoline.

6. A compound as claimed in claim 1 wherein Z is N-substitutedpiperazino of the formula:

-1-{ N ll R v 7. A compound as claimed in claim 6 wherein R is furyl. 8.A compound as claimed in claim 6 wherein R is thienyl. 9. A compound asclaimed in claim 6 wherein R is alkenyloxy having up to five carbonatoms.

10. A compound as claimed in claim 6 wherein R is alkoxy having from oneto six carbon atoms.

11. A compound as claimed in claim 6 wherein R is hydroxyalkoxy havingfrom two to six carbon atoms.

1 2. 2-[4-(2-Furoyl)-1-piperazinyl]-4-amino-6,7,8- trimethoxyquinazoline.

l3. Z-Methallyl 4-(4-amino-6,7,S-trimethoxyquinazolin-Z- yl)- l-piperazinecarboxylate.

l4. lsobutyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)- l-piperazinecarboxylate,

15. Z-Methyl-Z-hydroxypropyl 4-(4-amino-6,7,8-trimethoxyquinazoline-Z-yll -piperazinecarboxylate.

2. A compound as claimed in claim 1 wherein Z is monoalkylamino.
 3. Acompound as claimed in claim 1 wherein Z is di-alkylamino. 4.2-(N-Monomethylamino)-4-amino-6,7,8-trimethoxyquinazoline. 5.2-(N,N-Dimethylamino)-4-amino-6,7,8-trimethoxyquinazoline.
 6. A compoundas claimed in claim 1 wherein Z is N-substituted piperazino of theformula:
 7. A compound as claimed in claim 6 wherein R is furyl.
 8. Acompound as claimed in claim 6 wherein R is thienyl.
 9. A compound asclaimed in claim 6 wherein R is alkenyloxy having up to five carbonatoms.
 10. A compound as claimed in claim 6 wherein R is alkoxy havingfrom one to six carbon atoms.
 11. A compound as claimed in claim 6wherein R is hydroxyalkoxy having from two to six carbon atoms. 12.2-(4-(2-Furoyl)-1-piperazinyl)-4-amino-6,7,8-trimethoxyquinazoline. 13.2-Methallyl4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)-1-piperazinecarboxylate. 14.Isobutyl4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)-1-piperazinecarboxylate. 15.2-Methyl-2-hydroxypropyl4-(4-amino-6,7,8-trimethoxyquinazoline-2-yl)-1-piperazinecarboxylate.